The goal of this proposal is to determine the biological mechanisms that regulate male-typical sexual partner preference, and, thereby, to develop a better understanding of mammalian sexual differentiation and psychosexual development. The successful counseling of individuals who have issues and concerns related to their sexuality requires a comprehensive grasp of the biological underpinnings of human psychosexual development. However, clinical investigations of the contribution of fetal sex hormone exposure to sexual differentiation are limited to the study of extremely rare medical syndromes that are often difficult to interpret. Our studies address the critical need for a relevant animal model to further understanding of the etiology of neural mechanisms controlling mammalian sexual attraction. Thus, we will test the hypothesis that individual variations in adult mate recognition and neuroendocrine function of males depends on developmental events influencing the timing or extent of brain exposure to androgens. The ram is an exceptional model because variations in male-typical sexual partner preference occur spontaneously with as many as 8 percent of the population exhibiting a preference for same-sex mating partners (male-oriented rams). Sheep have a long period of gestation that closely approximates human fetal development making them an excellent experimental model for the study of possible links between fetal neuroendocrine programming and adult sexual behavior. We now know that the ovine sexually dimorphic nucleus (oSDN) is larger in rams that are attracted to females (female-oriented) than in male-oriented rams, and that it develops prior to birth. These results support the view that sexual preferences are hard-wired in the brain. However, the cellular and genetic mechanisms underlying these profound differences in oSDN architecture are unknown. Thus, our next critical step will be to establish the causal relationships between oSDN differentiation, adult function, and mate preferences. In our current working model, we hypothesize that testosterone acts directly through the androgen receptor pathway to protect developing oSDN neurons from undergoing programmed cell death. This, in turn, leads to the development of male-typical olfactory discrimination and sexual partner preference. Thus, we propose to: 1) test the hypothesis that oSDN volume and sexual partner preference are organized through an androgen receptor-mediated mechanism;2) test the hypothesis that neuronal apoptosis contributes to the sexual differentiation of the oSDN;3) test the hypothesis that chemosensory cues detected by the main olfactory bulb are necessary for the expression of sexual partner preferences in rams. Advancing the sheep model will provide a valuable animal system for research that bridges the central research interests of NICHD (mechanisms of steroid action in development of brain and behavior;NIMH (etiology of neural mechanisms that control a complex social behavior that is crucial to reproductive success);and NINDS (basic research to gain understanding the structure of the nervous system). PUBLIC HEALTH RELEVANCE: The successful counseling of individuals who have issues and concerns related to their sexuality would benefit from a comprehensive grasp of the biological underpinnings of human psychosexual development. However, clinical investigations of the contribution of fetal sex hormone exposure to sexual differentiation are limited to the study of extremely rare medical syndromes that are often difficult to interpret. Our studies address the critical need for a relevant animal model to further understanding of the etiology of neural mechanisms controlling mammalian sexual attraction. Thus, we will test the hypothesis that individual variations in adult mate recognition and neuroendocrine function of males depend on developmental events influencing the timing or extent of brain exposure to androgens.